We previously identified a retroviral env gene which is polymorphic among various mouse strains, having at least two alleles one of which is polytropic-like and one of which is xenotropic like (distinguished by monoclonal antibodies). The polytropic gp7O is expressed by mouse strains which are resistant to the induction of erythroleukemia induced by neonatal inoculation of F-MuLV and genetic analysis has shown that this resistance is in part due to the presence of this gene. We have found that the gp7O proteins encoded by these genes are expressed in normal mice by a population of cells which make up the pool of erythroid, granulocyte/monocyte and T-lymphocyte progenitors. We have extended these observations to the second allele of this gene, that which encodes a gp7O resembling that of xenotropic viruses. Genetic analysis also revealed that this gp7O functions as one of several resistance genes, which together impart resistance to erythroleukemia. The mechanism by which both of these alleles impart resistance to leukemogenesis involves restricting expression of recombinant polytropic viruses which appear to be the proximal agents in the induction of erythroleukemia. Viral interference has been proposed as the mechanism responsible for this form of genetic resistance to retroviral disease. We have tested this hypothesis in vitro and found that classical viral interference patterns are not induced by this env gene. We have now cloned one of these alleles (xenotropic-like) from a C-DNA library prepared from mouse 3T3 cell line derived in this laboratory. This sequence consists of approximately the 3' two thirds of an env gene plus the entire 3' LTR. Sequence comparison reveals a high level of homology with endogenous polytropic proviral sequences previously cloned from genomic DNA. This sequence has been introduced into a vaccinia expression system and the chimeric env protein will be analyzed to determine whether it reacts with the appropriate monoclonal antibodies. We have yet, however, to identify the 5' regulatory sequences which control expression of this gene.